This project addresses the overarching goals of the program project grant. The objective is to quantify the association between arteriosclerosis and changes in brain structure and function, taking into account measures of Alzheimer disease (AD) and cerebrovascular disease (CVD) pathology. Arteriosclerosis (AS) has well known relationships with ischemia, infarction, and hemorrhage and may have a role in the onset and progression of AD. However, our preliminary results suggest that AS has direct effects on brain parenchyma and hence cognition, independent of infarction and AD. We will explicitly evaluate alternate pathways by which arteriosclerosis can contribute to brain atrophy and cognitive impairment. Specific aim 1: In the autopsy subsample, we will quantify the association between cerebral cortical atrophy and executive function with the severity of arteriosclerosis, taking into account the severity of AD and CVD pathology. Specific aim 2: In the entire PPG sample, we will examine the relationship between arteriosclerosis and longitudinal change in cortical gray matter volume and executive cognitive function, using surrogate MRI measures to control for AD and CVD pathology. Specific aim 3: In exploratory analyses, we will evaluate the relationship between vascular risk profile and changes in brain structure and function. Specific aim 4: Finally, we will use all four modalities of vascular imaging, neuropsychology, MRI, and neuropathology to model the changes in AD and CVD pathology as a function of arteriosclerosis. The availability of longitudinal assessment with repeated quantitative neuroimaging and psychometrically-matched measures of cognition, together with neuropathology data, presents a unique opportunity to answer questions about how two major public health problems, AD and AS interact to cause brain injury and cognitive impairment.